This proposal is for a 5-year competing renewal of the University of Washington (UW) Superfund Research Program (SRP). The overarching theme of the program is to investigate the mechanisms and ramifications of metal neurotoxicity in humans and aquatic species. Based upon our work, we are developing biomarkers predictive of; 1) exposure to neurotoxic agents, 2) early indicators of neurotoxic injury at the cellular and organismal levels, and/or 3) genetic determinants that underlie unusual susceptibility to environmental neurotoxicants. The physiological processes under investigation adversely affect cognition, olfaction and neurobehavioral processes, and are associated with the risk of developing Alzheimer's and non-Alzheimer's related dementia, Parkinson?s disease, and other neurodevelopmental diseases. Our research focuses upon metals that commonly occur at Superfund hazardous waste sites for which there are important data gaps impeding the full understanding of their neurotoxic effects on human health and aquatic species. These data gaps include an understanding of mechanisms of toxicity, inter-individual or gender susceptibility, and biogeochemical factors that govern their fate in their environment. A key theme of our projects is addressing the role of cellular oxidative stress during metal-induced neurotoxicity. The UW program will include four research projects (two environmental science and two biomedical projects). The research projects include investigations of (1) mechanisms and biomarkers of metal olfactory injury to Pacific salmon, with a primary focus on cadmium; (2) cellular and molecular mechanisms of cadmium-mediated neurotoxicity in rodents, including effects on olfaction and cognition; (3) the role of paraoxonases as modifiers of cadmium and manganese neurotoxicity; and (4) biogeochemistry and bioavailability of arsenic in an urbanized lake system in Washington State. Our projects include collaborations among projects and cores, and each project is interdisciplinary in nature. The UW SRP includes a Training Core that is multi- and interdisciplinary, and will support predoctoral trainees from participating departments. The Research Translation Core will continue to ensure timely and appropriate communication of our research findings to NIEHS and other appropriate stakeholders, partner effectively with agencies, identify potential patents, and develop and support translation opportunities with other end-users of our scientific findings. The Community Engagement Core (a new Core beginning with 2015 funding) will build upon existing partnerships and expand partnerships with other communities, such as those directly affected by the toxicants we are studying, and with other community groups that have concerns about environmental toxicants. The Administrative Core will stimulate interactions among projects and cores ensuring full program integration, assure appropriate communication with NIEHS and other governmental agencies, oversee personnel and budgetary matters, and organize meetings and interactions with the Internal Executive Committee and the External Advisory Board.